6-(2-imidazolinylamino)quinoxaline compounds useful as alpha-2 adrenoceptor agonists

ABSTRACT

The subject invention relates to methods of treating alpha-2 adenoreceptor modulated disorders, comprising administration, to a mammal in need of such treatment, of a safe and effective amount of a compound having the following structure: ##STR1## wherein: (a) R is unsubstituted C 1  -C 3  alkanyl or alkenyl; and 
     (b) R&#39; is selected from hydrogen; unsubstituted C 1  -C 3  alkanyl or alkenyl; unsubstituted C 1  -C 3  alkylthio or alkoxy; hydroxy; thiol; and halo. 
     The subject invention also relates compounds and compositions for preventing or treating of disorders modulated by alpha-2 adrenoreceptors.

This is a continuation-in-part of application Ser. No. 08/496,707, filedon Jun. 29, 1995, now abandoned which is a continuation-in-part ofapplication Ser. No. 08/169,785, filed on Dec. 3, 1993 now abandoned.

TECHNICAL FIELD

The subject invention relates to certain substituted6-(2-imidazolinylamino)quinoxaline compounds. The compounds have beenfound to be alpha-2 adrenoceptor agonists and are useful for treatmentof disorders modulated by alpha-2 adrenoreceptors.

BACKGROUND OF THE INVENTION

Therapeutic indications of alpha-2 adrenoreceptor agonists have beendiscussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M.Stadel, & J. P. Hieble, "Pharmacologic and Therapeutic Applications ofAlpha-2 Adrenoceptor Subtypes", Annual Review of Pharmacology &Toxicology (1993) Vol. 32 pp. 243-279".

Information regarding alpha adrenergic receptors, agonists andantagonists, in general, and regarding compounds related in structure tothose of this invention are disclosed in the following references:Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, "12.1α-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol. 3,Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press(1990), pp. 133-185; Timmermans, P. B. M. W. M. & P. A. van Zwieten,"α-Adrenoceptor Agonists and Antagonists", Drugs of the Future, Vol. 9,No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F.H. L. Awouters & C. J. E. Niemegeers, "Further Validation of in vivo andin vitro Pharmacological Procedures for Assessing the α₁ and α₂-Selectivity of Test Compounds: (2) α-Adrenoceptor Agonists", EuropeanJournal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B.M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink & P.A. van Zwieten, "Quantitative Relationships between α-AdrenergicActivity and Binding Affinity of α-Adrenoceptor Agonists andAntagonists", Journal of Medicinal Chemistry, Vol. 27 (1984) pp.495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & P.A. van Zwieten, "Selectivity of Some Alpha Adrenoceptor Agonists forPeripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat",The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No.3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M.Myers, C. F. C. Smith & M. R. Stillings, "Effect of 1,4-DioxanylSubstitution on the Adrenergic Activity of Some Standardα-Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol.24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England,P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F.Tulloch, "Heteroaromatic Analogues of the α₂ -Adrenoreceptor PartialAgonist Clonidine", Journal of Medicinal Chemistry, Vol. 32 (1989), pp.1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson, "Effects of α₂-Adrenoceptor Agonists and of Related Compounds on Aggregation of, andon Adenylate Cyclase Activity in, Human Platelets", British Journal ofPharmacology, Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat.No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, manycompounds related in structure to those of this invention do not providethe activity and specificity desirable when treating disorders modulatedby alpha-2 adrenoreceptors.

For example, many compounds found to be effective nasal decongestantsare frequently found to have undesirable side effects, such as causinghypertension and insomnia at effective doses, particularly whenadministered systemically. There is a need for new drugs which providerelief from nasal congestion without causing these undesirable sideeffects.

OBJECTS OF THE INVENTION

It is an object of the invention to provide compounds and compositionsuseful in treating disorders modulated by alpha-2 adrenoreceptors.

It is an object of this invention to provide novel compounds havingsubstantial activity in preventing or treating nasal congestion, withoutundesired side effects.

It is also an object of this invention to provide novel compounds fortreating cough, chronic obstructive pulmonary disease (COPD) and/orasthma.

It is also an object of this invention to provide novel compounds fortreating diseases and disorders associated with sympathetic nervoussystem activity, including benign prostatic hypertrophy, cardiovasculardisorders comprising myocardial ischemia, cardiac reperfusion injury,angina, cardiac arrhythmia, heart failure and hypertension.

It is also an object of this invention to provide novel compounds fortreating ocular disorders, such as ocular hypertension, glaucoma,hyperemia, conjunctivitis and uveitis.

It is also an object of this invention to provide novel compounds fortreating gastrointestinal disorders, such as diarrhea, irritable bowelsyndrome, hyperchlorhydria and peptic ulcer, by antimotility andantisecretory actions on the gastrointestinal tract.

It is also an object of this invention to provide novel compounds fortreating migraine.

It is also an object of this invention to provide novel compounds fortreating pain, substance abuse and/or withdrawal. It is a still furtherobject of this invention to provide such compounds which have goodactivity from peroral, parenteral and/or topical dosing.

SUMMARY OF THE INVENTION

The subject invention relates to methods of treating nasal or preventivealpha-2 modulated disorders, comprising administration, to a mammal inneed of such treatment, of a safe and effective amount of a compoundhaving the following structure: ##STR2## wherein: (a) R is unsubstitutedC₁ -C₃ alkanyl or alkenyl; and

(b) R' is selected from hydrogen; unsubstituted C₁ -C₃ alkanyl oralkenyl; unsubstituted C₁ -C₃ alkylthio or alkoxy; hydroxy; thiol; andhalo.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "alkanyl" means a saturated hydrocarbon substituent,straight or branched chain, unsubstituted or substituted.

As used herein, "alkenyl" means a hydrocarbon substituent with onedouble bond, straight or branched chain, unsubstituted or substituted.

As used herein, "alkylthio" means a substituent having the structureQ--S--, where Q is alkanyl or alkenyl.

As used herein, "alkoxy" means a substituent having the structureQ--O--, where Q is alkanyl or alkenyl.

A "pharmaceutically-acceptable salt" is a cationic salt formed at anyacidic (e.g., carboxyl) group, or an anionic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987 (incorporated by reference herein). Preferred cationic saltsinclude the alkali metal salts (such as sodium and potassium), andalkaline earth metal salts (such as magnesium and calcium) and organicsalts. Preferred anionic salts include the halides (such as chloridesalts).

"Biohydrolyzable amide" refers to an amide of the compound of theinvention that is readily converted in vivo by a mammal subject to yieldan active compound of the invention.

A "biohydrolyzable ester" refers to an ester of the compound of theinvention that is readily converted by an animal to yield an activecompound of the invention.

"Optical isomer", "stereoisomer", "enantiomer," "diastereomer," asreferred to herein have the standard art recognized meanings (Cf.,Hawleys Condensed Chemical Dictionary, 11th Ed.). Of course, an additionsalt may provide an optical center, where once there was none. Forexample, a chiral tartrate salt may be prepared from the compounds ofthe invention, and this definition includes such chiral salts. It willbe apparent to the skilled artisan that disclosure of the racemicmixture alone discloses any enantiomers therein. Thus by one disclosure,more than one compound is taught.

As used herein "animal" includes "mammals" which includes "humans."Additionally a "lower animal" includes mammals other than man or"humans."

The skilled artisan will appreciate that tautomeric forms will exist incertain compounds of the invention. For example, when the2-iminoimidazolidinyl form of the molecule is shown, it is understood toinclude the 2-imidazolinylamino form of that molecule although notspecifically depicted. Thus, in this description the disclosure of onetautomeric form discloses each and all of the tautomers.

Compounds

The subject invention involves compounds having the followingstructures: ##STR3##

In the above structure, R is unsubstituted alkanyl or alkenyl havingfrom 1 to about 3 carbon atoms. R is preferably alkanyl. R is morepreferably methyl or ethyl, most preferably methyl.

In the above structure, R' is selected from hydrogen; unsubstitutedalkanyl or alkenyl having from 1 to about 3 carbon atoms; unsubstitutedalkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy;thiol; and halo. R' is preferably hydrogen. R' is also preferablyalkanyl, more preferably methyl or ethyl, most preferably methyl. R'which is alkylthio or alkoxy is preferably saturated, also preferably C₁or C₂, more preferably methylthio or methoxy. R' which is halo ispreferably chloro or bromo, more preferably chloro.

Preferred compounds of the subject invention are compounds having thefollowing structure: ##STR4## where R and R' are as indicated in thefollowing table:

    ______________________________________                                        Compound No.      R      R'                                                   ______________________________________                                        1                 CH.sub.3                                                                             H                                                    ______________________________________                                    

The compounds of the subject invention are synthesized using thefollowing general procedure: ##STR5##

It will be apparent to the skilled artisan that the reactionsillustrated above are known reactions. Furthermore, it is within thepurview of the skilled artisan to vary these reactions to preparecompounds within the scope of the claims.

In the above schemes, where an R is alkoxy or alkylthio, thecorresponding hydroxy or thiol compounds are derived from the finalcompounds by using a standard dealkylating procedure (Bhatt, et al.,"Cleavage of Ethers", Synthesis, 1983, pp. 249-281).

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available as astarting material.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March, AdvancedOrganic Chemistry (Wiley), Carey and Sundberg, Advanced OrganicChemistry (2 vol.) and Trost and Fleming Comprehensive Organic Synthesis(6 vol.). The skilled artisan will readily appreciate that certainreactions are best carried out when other functionality is masked orprotected in the molecule, thus avoiding any undesirable side reactionsand/or increasing the yield of the reaction. Often the skilled artisanutilizes protecting groups to accomplish such increased yields or toavoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations are found, for example, in T.Greene, Protecting Groups in Organic Synthesis.

The following non-limiting example provides details for the synthesis of6-(2-imidazolinylamino)quinoxaline compounds useful in the subjectinvention.

EXAMPLE 1 Synthesis of 6-(2-imidazolinylamino)-5-methylquinoxaline##STR6##

2,3-Diamino-6-nitrotoluene. To a solution of 3-methyl-2,4-dinitroaniline(30 g, prepared by the procedure of A. J. Boulton, P. B. Ghosh, A. R.Katritzky, J. Chem Soc. (B), 1011 (1966)) in boiling ethanol (750 mL) isadded dropwise over 90 minutes a solution of sodium sulfide nonahydrate(109.6 g) in water (750 mL). At the end of the addition, the mixture isrefluxed for 30 minutes then poured in ice (2000 g) and allowed to standuntil all the ice has melted. The mixture is then extracted withmethylene chloride and the organic layer is dried over magnesium sulfateand rotary evaporated. The residue is purified by flash chromatographyon silica gel, eluting with methylene chloride to afford2,3-diamino-6-nitrotoluene as an orange solid.

5-Methyl-6-nitroquinoxaline. To an 85° C. mixture of water (150 mL) and2,3-diamino-6-nitrotoluene (4.2 g) is added glyoxal sodium bisulfitecomplex (8.6 g). After two hours stirring, the mixture is cooled to roomtemperature, treated with solid sodium hydroxide until a pH of 12-13 isreached and extracted with a 9/1 mixture of chloroform/methanol (4×500mL). The combined organic layers are dried over potassium carbonate,filtered, and rotary evaporated to a residue which is vacuum sublimed at120° C. to give 5-methyl-6-nitroquinoxaline.

6-Amino-5-methylquinoxaline. A mixture of 5-methyl-6-nitroquinoxaline(1.4 g), ethanol (100 mL) and stannous chloride dihydrate (7.2 g) isheated at reflux for three hours, cooled to below room temperature in anice bath and treated with 1.0 N NaOH solution (120 mL). The mixture isthen extracted with chloroform (2×1000 mL). The combined extracts aredried over potassium carbonate, filtered, and rotary evaporated to give6-amino-5-methylquinoxaline.

6-(N'-Aminoethylthioureido)-5-methylquinoxaline. To a refluxing solutionof benzoyl isothiocyanate (1.6 g) in dry acetone (20 mL) is addeddropwise a solution of 6-amino-5-methylquinoxaline (1.2 g) in dryacetone (50 mL) over 30 minutes. The mixture is refluxed an additionaltwo hours, cooled to room temperature, and rotary evaporated to aresidue. This material is suspended in 10% NaOH solution (50 mL) forminga mixture which is heated at 90° C. for 30 minutes, then cooled to roomtemperature and adjusted to pH=8 by adding concentrated HCl. The mixtureis then cooled in an ice bath and suction filtered. The collected solidthiourea intermediate is dried on a vacuum line (16 h, 0.5 torr),suspended in bromobenzene (50 mL) and heated at reflux for six hours toeffect conversion to the isothiocyanate intermediate which is notisolated. The solution is cooled, then added dropwise to a solution ofethylene diamine (5.0 mL) in toluene (10 mL). The resulting mixture isstirred for 16 hours and filtered. The solids are washed with toluene(20 mL) and dried under vacuum to yield6-(N'-aminoethylthioureido)-5-methylquinoxaline.

6-(2-Imidazolinylamino)-5-methylquinoxaline. A solution of6-(N'-aminoethylthioureido)-5-methylquinoxaline (0.95 g) and mercuricacetate (1.22 g) in methanol (100 mL) is stirred at room temperature for3 hours, filtered through a pad of Celite which is subsequently rinsedwith methanol (2×300 mL). The combined methanol layers are rotaryevaporated to a residue which is crystallized from benzene to yield6-(2-imidazolinylamino)-5-methylquinoxaline. The mother liquor yields asecond crop upon partial evaporation and crystallization.

EXAMPLE 2 ##STR7## a. Combine 2-imidazolidinethione (5.0 grams) andabsolute ethanol (40 ml) while stirring. Rapidly add methyl iodide (4.3ml, 1.4 Eq). Warm the reaction mixture to 30° C.-35° C. The startingmaterial is consumed after 45 minutes.

b. Potassium carbonate (10.1 grams) is added to the mixture in (a)above, followed by addition of methyl chloroformate (4.2 ml) whilestirring. After 45 minutes, the reaction mixture is heated to 55° C. andthe insoluble salts are filtered off. These salts are washed with 10 mlabsolute ethanol. The filtrate (and ethanol wash) are cooled to -20 Cand the final product is isolated on a Buchner funnel. The final productis washed with 10 ml cold (-20 C) absolute ethanol. The product wasdried overnight under vacuum at room temperature, yieldingN-Carbomethoxy-2-thiomethyl-2-imidazoline.

c. The N-Carbomethoxy-2-thiomethyl-2-imidazoline is combined with theamine of Example 6-amino-5-methylquinoxaline in acetic acid andrefluxed. After starting amine is consumed, the mixture is decolorizedwith carbon. The product is cooled, filtered, dried and thenrecrystallized from acetonitrile and water. Upon drying, the compound ofExample 6-(2-Imidazolinylamino)-5-methylquinoxaline is obtained.

Compositions

Another aspect of this invention is compositions which comprise a safeand effective amount of a subject compound, or apharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable carrier.

As used herein, "safe and effective amount" means an amount of thesubject compound sufficient to significantly induce a positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. A safe and effective amount of thesubject compound will vary with the age and physical condition of thepatient being treated, the severity of the condition, the duration ofthe treatment, the nature of concurrent therapy, the particularpharmaceutically-acceptable carrier utilized, and like factors withinthe knowledge and expertise of the attending physician.

Preparing a dosage form is within the purview of the skilled artisan.Examples are provided for the skilled artisan, but are non-limiting, andit is contemplated that the skilled artisan can prepare variations ofthe compositions claimed.

Compositions of this invention preferably comprise from about 0.0001% toabout 99% by weight of the subject compound, more preferably from about0.01% to about 90% of the compound of the invention. Depending upon theroute of administration and attendant bioavailability, solubility ordissolution characteristics of the dosage form, the dosage form haspreferably from about 10% to about 50%, also preferably from about 5% toabout 10%, also preferably from about 1% to about 5%, and alsopreferably from about 0.01% to about 1% of the subject compound.

In addition to the subject compound, the compositions of this inventioncontain a pharmaceutically-acceptable carrier. The term"pharmaceutically-acceptable carrier", as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a mammal. The term"compatible", as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Preferably when liquid doseforms are used, the compounds of the invention are soluble in thecomponents of the composition. Pharmaceutically-acceptable carriersmust, of course, be of sufficiently high purity and sufficiently lowtoxicity to render them suitable for administration to the mammal beingtreated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens®; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered. For indications other than oculardisorders, the preferred route of administration is peroral. Thepreferred route of administration for ocular disorders is intraocularly,such as by eyedrop or the like.

If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with a blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

The preferred mode of administering the subject compounds is perorally.The preferred unit dosage form is therefore tablets, capsules, lozenges,chewable tablets, and the like. Such unit dosage forms comprise a safeand effective amount of the subject compound, which is preferably fromabout 0.01 mg to about 200 mg, more preferably from about 0.1 mg toabout 50 mg, more preferably still from about 0.5 mg to about 25 mg,also preferably from about 1 mg to about 10 mg. Thepharmaceutically-acceptable carrier suitable for the preparation of unitdosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of thisinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Such liquid oral compositions preferably comprise from about 0.001% toabout 5% of the subject compound, more preferably from about 0.01% toabout 0.5%. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol,polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose, Avicel® RC-591, tragacanth and sodium alginate;typical wetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual and buccal dosage forms. Such compositionstypically comprise one or more of soluble filler substances such assucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

An also preferred mode of administering the subject compounds istopically to the site where activity is desired: intranasal doses fornasal decongestion, inhalants for asthma, eye drops, gels and creams forocular disorders, and peroral doses for gastrointestinal disorders.

Preferred topical compositions of this invention include solutions oremulsions, preferably aqueous solutions or emulsions comprising a safeand effective amount of a subject compound intended for topicalintranasal administration. Such compositions preferably comprise fromabout 0.001% to about 25% of a subject compound, more preferably fromabout 0.01% to about 10%. Such compositions also typically include safeand effective amounts of preservatives, such as benzalkonium chlorideand thimerosal and the like; chelating agents, such as edetate sodiumand others; buffers such as phosphate, citrate and acetate; tonicityagents such as sodium chloride, potassium chloride, glycerin, mannitoland others; antioxidants such as ascorbic acid, acetylcystine, sodiummetabisulfate and others; aromatic agents; viscosity adjustors, such aspolymers, including cellulose and derivatives thereof, and polyvinylalcohol and acids and bases to adjust the pH of these aqueouscompositions as needed. The compositions may also comprise localanesthetics or other actives. These compositions can be used as sprays,mists, drops, and the like.

Other preferred compositions of this invention include aqueoussolutions, suspensions, and dry powders comprising a safe and effectiveamount of a subject compound intended for atomization and topicalinhalation administration. Such compositions preferably comprise fromabout 0.1% to about 50% of a subject compound, more preferably fromabout 1% to about 20%; of course, the amount can be altered to fit thecircumstance of the patient contemplated and the package. Suchcompositions are typically contained in a container with attachedatomizing means. Such compositions also typically include propellantssuch as chlorofluorocarbons 12/11 and 12/114, and more environmentallyfriendly fluorocarbons, or other nontoxic volitiles; solvents such aswater, glycerol and ethanol, these include cosolvents as needed tosolvate or suspend the active; stabilizers such as ascorbic acid, sodiummetabisulfite; preservatives such as cetylpyridinium chloride andbenzalkonium chloride; tonicity adjustors such as sodium chloride;buffers; and flavoring agents such as sodium saccharin. Suchcompositions are useful for treating respiratory disorders, such asasthma and the like.

Other preferred compositions of this invention include aqueous solutionscomprising a safe and effective amount of a subject compound intendedfor topical intraocular administration. Such compositions preferablycomprise from about 0.0001% to about 5% of a subject compound, morepreferably from about 0.01% to about 0.5%. Such compositions alsotypically include one or more of preservatives, such as benzalkoniumchloride, thimerosal, phenylmercuric acetate; vehicles, such aspoloxamers, modified celluloses, povidone and purified water; tonicityadjustors, such as sodium chloride, mannitol and glycerin; buffers suchas acetate, citrate, phosphate and borate; antioxidants such as sodiummetabisulfite, butylated hydroxy toluene and acetyl cysteine; acids andbases may be used to adjust the pH of these formulations as needed.

Other preferred compositions of this invention useful for peroraladministration include solids, such as tablets and capsules, andliquids, such as solutions, suspensions and emulsions (preferably insoft gelatin capsules), comprising a safe and effective amount of asubject compound intended for topical administration to thegastrointestinal tract by peroral administration. Such compositionspreferably comprise from about 0.01 mg to about 100 mg per dose, morepreferably from about 0.1 mg to about 5 mg per dose. Such compositionscan be coated by conventional methods, typically with pH ortime-dependent coatings, such that the subject compound is released inthe gastrointestinal tract in the vicinity of the desired topicalapplication, or at various times to extend the desired action. Suchdosage forms typically include, but are not limited to, one or more ofcellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose, Eudragit® coatings, waxesand shellac.

Any of the compositions of this invention may optionally include otherdrug actives. Non-limiting examples of drug actives which may beincorporated in these compositions, include:

Antihistamines, including;

Hydroxyzine preferably at a dosage range of from about 25 to about 400mg; Doxylamine, preferably at a dosage range of from about 3 to about 75mg; Pyrilamine, preferably at a dosage range of from about 6.25 to about200 mg; Chlorpheniramine, preferably at a dosage range of from about 1to about 24 mg; Phenindamine, preferably at a dosage range of from about6.25 to about 150 mg; Dexchlorpheniramine, preferably at a dosage rangeof from about 0.5 to about 12 mg; Dexbrompheniramine, preferably at adosage range of from about 0.5 to about 12 mg; Clemastine, preferably ata dosage range of from about 1 to about 9 mg; Diphenhydramine,preferably at a dosage range of from about 6.25 to about 300 mg;Azelastine, preferably at a dosage range of from about 140 to about1,680 ug (when dosed intranasally); 1 to about 8 mg (when dosed orally);Acrivastine, preferably at a dosage range of from about 1 to about 24mg; Levocarbastine (which can be dosed as an intranasal or ocularmedicament), preferably at a dosage range of from about 100 to about 800mg; Mequitazine, preferably at a dosage range of from about 5 to about20 mg; Astemizole, preferably at a dosage range of from about 5 to about20 mg; Ebastine; Loratadine, preferably at a dosage range of from about5 to about 40 mg; Cetirizine, preferably at a dosage range of from about5 to about 20 mg; Terfenadine, preferably at a dosage range of fromabout 30 to about 480 mg; Terfenadine metabolites; Promethazine,preferably at a dosage range of from about 6.25 to about 50 mg;Dimenhydrinate, preferably at a dosage range of from about 12.5 to about400 mg; Meclizine, preferably at a dosage range of from about 6.25 toabout 50 mg; Tripelennamine, preferably at a dosage range of from about6.25 to about 300 mg; Carbinoxamine, preferably at a dosage range offrom about 0.5 to about 16 mg; Cyproheptadine, preferably at a dosagerange of from about 2 to about 20 mg; Azatadine, preferably at a dosagerange of from about 0.25 to about 2 mg; Brompheniramine, preferably at adosage range of from about 1 to about 24 mg; Triprolidine, preferably ata dosage range of from about 0.25 to about 10 mg; Cyclizine, preferablyat a dosage range of from about 12.5 to about 200 mg; Thonzylamine,preferably at a dosage range of from about 12.5 to about 600 mg;Pheniramine, preferably at a dosage range of from about 3 to about 75mg; Cyclizine, preferably at a dosage range of from about 12.5 to about200 mg and others;

Antitussives, including;

Codeine, preferably at a dosage range of from about 2.5 to about 120 mg;Hydrocodone, preferably at a dosage range of from about 2.5 to about 40mg; Dextromethorphan, preferably at a dosage range of from about 2.5 toabout 120 mg; Noscapine, preferably at a dosage range of from about 3 toabout 180 mg; Benzonatate, preferably at a dosage range of from about100 to about 600 mg; Diphenhydramine, preferably at a dosage range offrom about 12.5 to about 150 mg; Chlophedianol, preferably at a dosagerange of from about 12.5 to about 100 mg; Clobutinol, preferably at adosage range of from about 20 to about 240 mg; Fominoben, preferably ata dosage range of from about 80 to about 480 mg; Glaucine; Pholcodine,preferably at a dosage range of from about 1 to about 40 mg; Zipeprol,preferably at a dosage range of from about 75 to about 300 mg;Hydromorphone, preferably at a dosage range of from about 0.5 to about 8mg; Carbetapentane, preferably at a dosage range of from about 15 toabout 240 mg; Caramiphen, Levopropoxyphene, preferably at a dosage rangeof from about 25 to about 200 mg and others;

Antiinflammatories, preferably Non-Steroidal Anti-inflammatories,(NSAIDS) including;

Ibuprofen, preferably at a dosage range of from about 50 to about 3,200mg; Naproxen, preferably at a dosage range of from about 62.5 to about1,500 mg; Sodium naproxen, preferably at a dosage range of from about110 to about 1,650 mg; Ketoprofen, preferably at a dosage range of fromabout 25 to about 300 mg; Indoprofen, Indomethacin, preferably at adosage range of from about 25 to about 200 mg; Sulindac, preferably at adosage range of from about 75 to about 400 mg; Diflunisal, preferably ata dosage range of from about 125 to about 1,500 mg; Ketorolac,preferably at a dosage range of from about 10 to about 120 mg;Piroxicam, preferably at a dosage range of from about 10 to about 40 mg;Aspirin, preferably at a dosage range of from about 80 to about 4,000mg; Meclofenamate, preferably at a dosage range of from about 25 toabout 400 mg; Benzydamine, preferably at a dosage range of from about 25to about 200 mg; Carprofen, preferably at a dosage range of from about75 to about 300 mg; Diclofenac, preferably at a dosage range of fromabout 25 to about 200 mg; Etodolac, preferably at a dosage range of fromabout 200 to about 1,200 mg; Fenbufen, preferably at a dosage range offrom about 300 to about 900 mg; Fenoprofen, preferably at a dosage rangeof from about 200 to about 3,200 mg; Flurbiprofen, preferably at adosage range of from about 50 to about 300 mg; Mefenamic acid,preferably at a dosage range of from about 250 to about 1,500 mg;Nabumetone, preferably at a dosage range of from about 250 to about2,000 mg; Phenylbutazone, preferably at a dosage range of from about 100to about 400 mg; Pirprofen, preferably at a dosage range of from about100 to about 800 mg; Tolmetin, preferably at a dosage range of fromabout 200 to about 1,800 mg and others;

Analgesics, including;

Acetaminophen, preferably at a dosage range of from about 80 to about4,000 mg; and others:

Expectorants/Mucolytics, including;

Guaifenesin, preferably at a dosage range of from about 50 to about2,400 mg; N-Acetylcysteine, preferably at a dosage range of from about100 to about 600 mg; Ambroxol, preferably at a dosage range of fromabout 15 to about 120 mg; Bromhexine, preferably at a dosage range offrom about 4 to about 64 mg; Terpin hydrate, preferably at a dosagerange of from about 100 to about 1,200 mg; Potassium iodide, preferablyat a dosage range of from about 50 to about 250 mg and others;

Anticholinergics (e.g., Atropinics), preferably intranasally or orallyadministered anticholinergics, including;

Ipratroprium (preferably intranasally), preferably at a dosage range offrom about 42 to about 252 Atropine sulfate (preferably oral),preferably at a dosage range of from about 10 to about 1,000 μg;Belladonna (preferably as an extract), preferably at a dosage range offrom about 15 to about 45 mg equivalents; Scopolamine, preferably at adosage range of from about 400 to about 3,200 μg; Scopolaminemethobromide, preferably at a dosage range of from about 2.5 to about 20mg; Homatropine methobromide, preferably at a dosage range of from about2.5 to about 40 mg; Hyoscyamine (preferably oral), preferably at adosage range of from about 125 to about 1,000 μg; Isopropramide(preferably oral), preferably at a dosage range of from about 5 to about20 mg; Orphenadrine (preferably oral), preferably at a dosage range offrom about 50 to about 400 mg; Benzalkonium chloride (preferablyintranasally) preferably a 0.005 to about 0.1% solution and others;

Mast Cell Stabilizers, preferably intranasally, or orally administeredmast cell stabilizers, including;

Cromalyn, preferably at a dosage range of from about 10 to about 60 mg;Nedocromil, preferably at a dosage range of from about 10 to about 60mg; Oxatamide, preferably at a dosage range of from about 15 to about120 mg; Ketotifen, preferably at a dosage range of from about 1 to about4 mg; Lodoxamide, preferably at a dosage range of from about 100 toabout 3,000 μg and others;

LT Antagonists, including Zileuton and others;

Methylxanthines, including;

Caffeine, preferably at a dosage range of from about 65 to about 600 mg;Theophyllene, preferably at a dosage range of from about 25 to about1,200 mg; Enprofylline; Pentoxifylline, preferably at a dosage range offrom about 400 to about 3,600 mg; Aminophylline, preferably at a dosagerange of from about 50 to about 800 mg; Dyphylline, preferably at adosage range of from about 200 to about 1,600 mg and others;

Antioxidants or radical inhibitors, including;

Ascorbic acid, preferably at a dosage range of from about 50 to about10,000 mg; Tocopherol, preferably at a dosage range of from about 50 toabout 2,000 mg; Ethanol, preferably at a dosage range of from about 500to about 10,000 mg and others;

Steroids, Preferably intranasally administered steroids, including;

Beclomethasone, preferably at a dosage range of from about 84 to about336 μg; Fluticasone, preferably at a dosage range of from about 50 toabout 400 μg; Budesonide, preferably at a dosage range of from about 64to about 256 μg; Mometasone; Triamcinolone, preferably at a dosage rangeof from about 110 to about 440 μg; Dexamethasone, preferably at a dosagerange of from about 168 to about 1,008 μg; Flunisolide, preferably at adosage range of from about 50 to about 300 μg; Prednisone (preferablyoral), preferably at a dosage range of from about 5 to about 60 mg;Hydrocortisone (preferably oral), preferably at a dosage range of fromabout 20 to about 300 mg and others;

Bronchodilators, Preferably for inhalation, including;

Albuterol, preferably at a dosage range of from about 90 to about 1,080μg; 2 to about 16 mg (if dosed orally); Epinephrine, preferably at adosage range of from about 220 to about 1,320 μg; Ephedrine, preferablyat a dosage range of from about 15 to about 240 mg (if dosed orally);250 to about 1,000 μg (if dosed intranasally); Metaproterenol,preferably at a dosage range of from about 65 to about 780 μg or 10 toabout 80 mg if dosed orally; Terbutaline, preferably at a dosage rangeof from about 200 to about 2,400 μg; 2.5 to about 20 mg if dosed orally;Isoetharine, preferably at a dosage range of from about 340 to about1,360 μg; Pirbuterol, preferably at a dosage range of from about 200 toabout 2,400 μg; Bitolterol, preferably at a dosage range of from about370 to about 2,220 μg; Fenoterol, preferably at a dosage range of fromabout 100 to about 1,200 μg; 2.5 to about 20 mg (if dosed orally);Rimeterol, preferably at a dosage range of from about 200 to about 1,600μg; Ipratroprium, preferably at a dosage range of from about 18 to about216 μg (inhalation) and others; and

Antivirals, including;

Amantadine, preferably at a dosage range of from about 50 to about 200mg; Rimantadine, preferably at a dosage range of from about 50 to about200 mg; Enviroxime; Nonoxinols, preferably at a dosage range of fromabout 2 to about 20 mg (preferably an intranasal form); Acyclovir,preferably at a dosage range of from about 200 to about 2,000 mg (oral);1 to about 10 mg (preferably an intranasal form); Alpha-Interferon,preferably at a dosage range of from about 3 to about 36 MIU;Beta-Interferon, preferably at a dosage range of from about 3 to about36 MIU and others;

Ocular Drug actives: acetylcholinesterase inhibitors, e.g.,echothiophate from about 0.03% to about 0.25% in topical solution andothers; and

Gastrointestinal actives: antidiarrheals, e.g., loperamide from about0.1 mg to about 1.0 mg per dose, and bismuth subsalicylate from about 25mg to about 300 mg per dose and others.

Of course, clearly contemplated and included in the description aboveare the acid or base addition salts, esters, metabolites, stereoisomersand enantiomers of these preferred combination actives, as well as theiranalogues of these actives that are safe and effective. It is alsorecognized that an active may be useful for more than one of the aboveuses, and these uses are clearly contemplated as well. This overlap isrecognized in the art and adjusting dosages and the like to fit theindication is well within the purview of the skilled medicalpractitioner.

Methods of Use

Without being bound by theory, it is contemplated that the primarymechanism by which alpha-2 agonists provide efficacy is by interveningin the biochemical cascade responsible for disorder(s) and/ormanifestation(s) thereof. It may be that there is no deficit in alpha-2adrenoreceptor activity: such activity may be normal. However,administration of an alpha-2 agonist may be a useful way of rectifying adisorder, condition or manifestation thereof.

Thus as used herein, the terms "disease," "disorder" and "condition" areused interchangeably to refer to maladies related to or modulated byalpha-2 adrenoreceptor activity.

As used herein, a disorder described by the terms "modulated by alpha-2adrenoreceptors," or "modulated by alpha-2 adrenoreceptor activity"refers to a disorder, condition or disease where alpha-2 adrenoreceptoractivity is an effective means of alleviating the disorder or one ormore of the biological manifestations of the disease or disorder; orinterferes with one or more points in the biological cascade eitherleading to the disorder or responsible for the underlying disorder; oralleviates one or more symptoms of the disorder. Thus, disorders subjectto "modulation" include those for which:

The lack of alpha-2 activity is a "cause" of the disorder or one or moreof the biological manifestations, whether the activity was alteredgenetically, by infection, by irritation, by internal stimulus or bysome other cause;

The disease or disorder or the observable manifestation ormanifestations of the disease or disorder are alleviated by alpha-2activity. The lack of alpha-2 activity need not be causally related tothe disease or disorder or the observable manifestations thereof;

Alpha-2 activity interferes with part of the biochemical or cellularcascade that results in or relates to the disease or disorder. In thisrespect, the alpha-2 activity alters the cascade, and thus controls thedisease, condition or disorder.

The compounds of this invention are particularly useful for thetreatment of nasal congestion associated with allergies, colds, andother nasal disorders with associated nasal congestion, as well as theirsequelae (for example, sinusitis and otitis). At effective doses, it hasbeen found that undesired side effects can be avoided.

While not limited to a particular mechanism of action, the subjectcompounds are believed to provide advantages in the treatment of nasaldecongestion over related compounds through their ability to interactwith alpha-2 adrenoceptors. The subject compounds have been found to bealpha-2 adrenoceptor agonists which cause constriction of peripheralvascular beds in the turbinates.

Alpha-2 adrenoreceptors are distributed both inside and outside of thecentral nervous system. Thus, though not essential for activity orefficacy, certain disorders preferably are treated with compounds thatact on alpha-2 adrenoreceptors in only one of these regions. Compoundsof this invention vary in their ability to penetrate into the centralnervous system and, thus, to produce effects mediated through centralalpha-2 adrenoreceptors. Thus, for example, a compound which displays ahigher degree of central nervous system activity is preferred forcentral nervous system indications over other compounds as describedbelow. However, even for compounds that exhibit primarily peripheralactivity, central nervous system actions can be evoked by an increase inthe dose of the compound. Further specificity of action of thesecompounds can be achieved by delivering the agent to the region whereactivity is desired (for example, topical administration to the eye,nasal mucosa or respiratory tract).

Compounds preferred for, but not limited to, the treatment of certaincardiovascular disorders, pain, substance abuse and/or withdrawal, ulcerand hyperacidity include those compounds that are centrally acting. Bycentrally acting what is meant is that they have some action on thealpha-2 adrenoreceptors in the central nervous system in addition totheir action at peripheral alpha-2 adrenoreceptors.

Compounds preferred for, but not limited to, the treatment ofrespiratory disorders, ocular disorders, migraine, certaincardiovascular disorders, and certain other gastrointestinal disordersare peripherally acting. By peripherally acting, what is meant is thatthese compounds act primarily on alpha-2 adrenoreceptors in theperiphery, rather than those in the central nervous system. Methods areavailable in the art to determine which compounds are peripherallyacting and which are centrally acting.

Thus, compounds of the subject invention are also useful for thetreatment of ocular disorders such as ocular hypertension, glaucoma,hyperemia, conjunctivitis, and uveitis. The compounds are administeredeither perorally, or topically as drops, sprays, mists, gels or creamsdirectly to the surface of the mammalian eye.

The compounds of this invention are also useful for controllinggastrointestinal disorders, such as diarrhea, irritable bowel syndrome,hyperchlorhydria and peptic ulcer, by antimotility and antisecretoryactions on the gastrointestinal tract.

The compounds of this invention are also useful for diseases anddisorders associated with sympathetic nervous system activity, includinghypertension, myocardial ischemia, cardiac reperfusion injury, angina,cardiac arrhythmia, heart failure and benign prostatic hypertrophy. Dueto their sympatholytic effect, compounds may prove useful as an adjunctto anesthesia during surgical procedures.

The compounds of this invention are also useful for relieving painassociated with various disorders. The compounds are administeredperorally, parenterally, and/or by direct injection into thecerebrospinal fluid.

The compounds of this invention are also useful for the prophylactic oracute treatment of migraine. The compounds are administered perorally,intranasally, or parenterally.

The compounds of this invention are also useful for treatment ofsubstance abuse, in particular abuse of alcohol and opiates, andalleviating the abstinence syndromes evoked by withdrawal of thesesubstances.

The compounds of this invention are also useful for other diseases anddisorders where vasoconstriction, particularly of veins, would provide abenefit, including septic or cardiogenic shock, elevated intracranialpressure, hemmorhoids, venous insufficiency, varicose veins, andmenopausal flushing.

The compounds of this invention are also useful for neurologic diseasesand disorders, including spasticity, epilepsy, attention deficithyperactive disorder, Tourette's syndrome, and cognitive disorders.

The pharmacological activity and selectivity of these compounds can bedetermined using published test procedures. The alpha-2 selectivity ofthe compounds is determined by measuring receptor binding affinities andin vitro functional potencies in a variety of tissues known to possessalpha-2 and/or alpha-1 receptors. (See, e.g., The Alpha-2 AdrenergicReceptors, L. E. Limbird, ed., Humana Press, Clifton, N.J.) Thefollowing in vivo assays are typically conducted in rodents or otherspecies. Central nervous system activity is determined by measuringlocomotor activity as an index of sedation. (See, e.g., Spyraki, C. & H.Fibiger, "Clonidine-induced Sedation in Rats: Evidence for Mediation byPostsynaptic Alpha-2 Adrenoreceptors", Journal of Neural Transmission,Vol. 54 (1982), pp. 153-163). Nasal decongestant activity is measuredusing rhinomanometry as an estimate of nasal airway resistance. (See,e.g., Salem, S. & E. Clemente, "A New Experimental Method for EvaluatingDrugs in the Nasal Cavity", Archives of Otolaryngology, Vol. 96 (1972),pp. 524-529). Antiglaucoma activity is determined by measuringintraocular pressure. (See, e.g., Potter, D., "Adrenergic Pharmacologyof Aqueous Human Dynamics", Pharmacological Reviews, Vol. 13 (1981), pp.133-153). Antidiarrheal activity is determined by measuring the abilityof the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g.,Thollander, M., P. Hellstrom & T. Svensson, "Suppression of CastorOil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists", AlimentaryPharmacology and Therapeutics, Vol. 5 (1991), pp. 255-262). Efficacy intreating irritable bowel syndrome is determined by measuring the abilityof compounds to reduce the stress-induced increase in fecal output.(See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro &H. Ormsbee III, "Cold-restraint stress increases rat fecal pellet outputand colonic transit", American Journal of Physiology Vol. 258 (1990),pp. G329-G337). Antiulcer and reduction of hyperchlorhydria efficacy isdetermined by measuring the reduction in gastric acid secretion producedby these compounds (See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca &C. Roze, "Effect of α2-adrenoceptor agonists on gastric pepsin and acidsecretion in the rat", British Journal of Pharmacology Vol. 106 (1992),pp. 790-796). Antiasthma activity is determined by measuring the effectof the compound on bronchoconstriction associated with pulmonarychallenges such as inhaled antigens. (See, e.g., Chang, J. J. Musser &J. Hand, "Effects of a Novel Leukotriene D₄ Antagonist with5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, onLeukotriene-D4- and Antigen-Induced Bronchoconstriction in Guinea Pig",International Archives of Allergy and Applied Immunology, Vol. 86(1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger, B.Marchette, J. Stevenson & W. Abraham, "The Role of Slow-ReactingSubstance of Anaphylaxis in the Late Bronchial Response After AntigenChallenge in Allergic Sheep", American Reviews of Respiratory Disease.,Vol. 130 (1984), pp. 748-754). Activity in cough is determined bymeasuring the number and latency of the cough response to respiratorychallenges such as inhaled citric acid. (See, e.g., Callaway, J. & R.King, "Effects of Inhaled α2-Adrenoceptor and GABA_(B) Receptor Agonistson Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs",European Journal of Pharmacology, Vol. 220 (1992), pp. 187-195). Thesympatholytic activity of these compounds is determined by measuring thereduction of plasma catecholamines (See, e.g., R. Urban, B. Szabo & K.Starke "Involvement of peripheral presynaptic inhibition in thereduction of sympathetic tone by moxonidine, rilmenidine and UK 14,304",European Journal of Pharmacology Vol. 282 (1995), pp. 29-37) or thereduction in renal sympathetic nerve activity (See, e.g., Feng, Q., S.Carlsson, P. Thoren & T. Hedner, "Effects of clonidine on renalsympathetic nerve activity, natriuresis and diuresis in chroniccongestive heart failure rats", Journal of Pharmacology and ExperimentalTherapeutics, Vol. 261 (1992), pp. 1129-1135), providing the basis fortheir benefit in heart failure and benign prostatic hypertrophy. Thehypotensive effect of these compounds is measure directly as a reductionin mean blood pressure (See, e.g., Timmermans, P. & P. Van Zwieten,"Central and peripheral α-adrenergic effects of some imidazolidines",European Journal of Pharmacology, Vol. 45 (1977), pp. 229-236). Clinicalstudies have demonstrated the beneficial effect of alpha-2 agonists inthe prevention of myocardial ischemia during surgery (See, e.g., Talke,P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D. Mangano,"Effects of Perioperative Dexmedetomidine Infusion in PatientsUndergoing Vascular Surgery", Anesthesiology Vol. 82 (1995), pp.620-633) and in the prevention of angina (See, e.g., Wright, R. A., P.Decroly, T. Kharkevitch & M. Oliver, "Exercise Tolerance in Angina isImproved by Mivazerol--an α2-Adrenoceptor Agonist", Cardiovascular Drugsand Therapy Vol. 7 (1993), pp. 929-934). The efficacy of these compoundsin cardiac reperfusion injury is demonstrated by measuring the reductionof cardiac necrosis and neutrophil infiltration (See, e.g., Weyrich, A.,X. Ma, & A. Lefer, "The Role of L-Arginine in Ameliorating ReperfusionInjury After Myocardial Ischemia in the Cat", Circulation Vol. 86(1992), pp. 279-288). The cardiac antiarrhythmic effect of thesecompounds is demonstrated by measuring the inhibition of oubain inducedarrhythmias (See, e.g., Thomas, G. & P. Stephen, "Effects of TwoImidazolines (ST-91 and ST-93) on the Cardiac Arrhythmias and LethalityInduced by Ouabain in Guinea-Pig", Asia-Pacific Journal of Pharmacology,Vol. 8 (1993), pp.109-113; and Samson, R., J. Cai, E. Shibata, J.Martins & H. Lee, "Electrophysiological effects of α2-adrenergicstimulation in canine cardiac Purkinje fibers", American Journal ofPhysiology Vol. 268 (1995), pp. H2024-H2035). The vasoconstrictoractivity of these compounds is demonstrated by measuring the contractileproperties on isolated arteries and veins in vitro (See, e.g., Flavahan,N., T. Rimele, J. Cooke & M. Vanhoutte, "Characterization ofPostjunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenousor Nerve-Released Norepinephrine in the Canine Saphenous Vein", Journalof Pharmacology and Experimental Therapeutics Vol. 230 (1984), pp.699-705). The effectiveness of these compounds at reducing intracranialpressure is demonstrated by measurement of this property in a caninemodel of subarachnoid hemorrhage (See, e.g., McCormick, J., P.McCormick, J. Zabramski & R. Spetzler, "Intracranial pressure reductionby a central alpha-2 adrenoreceptor agonist after subarachnoidhemorrhage", Neurosurgery, Vol. 32 (1993), pp. 974-979). The inhibitionof menopausal flushing is demonstrated by measuring the reduction offacial blood flow in the rat (See, e.g., Escott, K., D. Beattie, H.Connor & S. Brain, "The modulation of the increase in rat facial skinblood flow observed after trigeminal ganglion stimulation", EuropeanJournal of Pharmacology, Vol. 284 (1995), pp. 69-76) as demonstrated foralpha-2 adrenergic agonists on cutaneous blood flow in the tail (See,e.g., Redfern, W., M. MacLean, R. Clague & J. McGrath, "The role ofalpha-2 adrenoceptors in the vasculature of the rat tail", BritishJournal of Pharmacology, Vol. 114 (1995), pp. 1724-1730). Theantinociceptive and pain reducing properties of these compounds isdemonstrated by measuring the increase in pain threshold in the rodentwrithing and hot plate antinociceptive models (See, e.g., Millan, M., K.Bervoets, J. Rivet, R. Widdowson, A. Renouard, S, Le Marouille-Girardon& A. Gobert, "Multiple Alpha-2 Adrenergic Receptor Subtypes. II.Evidence for a Role of Rat R_(Alpha-2A) Adrenergic Receptors in theControl of Nociception, Motor Behavior and Hippocampal Synthesis ofNoradrenaline", Journal of Pharmacology and Experimental TherapeuticsVol. 270 (1994), pp. 958-972). The antimigraine effect of thesecompounds is demonstrated by measuring the reduction of dural neurogenicinflammation to trigeminal ganglion stimulation in the rat (See, e.g.,Matsubara, T., M. Moskowitz & Z. Huang, "UK-14,304,R(-)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakagewithin dura mater by prejunctional mechanisms", European Journal ofPharmacology Vol. 224 (1992), pp. 145-150). The ability of thesecompounds to suppress opiate withdrawal is demonstrated by measuring thesuppression of enhanced sympathetic nerve activity (See, e.g., Franz,D., D. Hare & K. McCloskey, "Spinal sympathetic neurons: possible sitesof opiate-withdrawal suppression by clonidine", Science. Vol. 215(1982), pp. 1643-1645). Antiepileptic activity of these compounds candemonstrated by measuring the inhibition of the kindling response (See,e.g., Shouse, M., M. Bier, J. Langer, O. Alcalde, M. Richkind & R.Szymusiak, "The α2-agonist clonidine suppresses seizures, whereas thealpha-2 antagonist idazoxan promotes seizures--a microinfusion study inamygdala-kindled kittens", Brain Research Vol. 648 (1994), pp. 352-356).The effectiveness of other alpha-2 agonists in the management ofneurologic disorders has been demonstrated, including attention-deficithyperactive disorder and Tourette's syndrome (See, e.g., Chappell P., M.Riddle, L. Scahill, K. Lynch, R. Schultz, A. Arnsten, J. Leckman & D.Cohen, "Guanfacine treatment of comorbid attention-deficit hyperactivitydisorder and Tourette's syndrome: preliminary clinical experience",Journal of American Academy of Child and Adolescent Psychiatry, Vol. 34(1995), pp. 1140-1146), cognitive disorders (See, e.g., Coull, J.,"Pharmacological manipulations of the α2-noradrenergic system. Effectson cognition", Drugs and Aging, Vol. 5 (1994), pp. 116-126), andspasticity (See, e.g., Eyssette, M., F. Rohmer, G. Serratrice, J. Warter& D. Boisson, "Multicenter, double-blind trial of a novel antispasticagent, tizanidine, in spasticity associated with multiple sclerosis",Current Medical Research & Opinion Vol. 10 (1988), pp. 699-708).

Another aspect of this invention involves methods for preventing ortreating nasal congestion by administering a safe and effective amountof a subject compound to a mammal experiencing or at risk ofexperiencing nasal congestion. Such nasal congestion may be associatedwith human diseases or disorders which include, but are not limited to,seasonal allergic rhinitis, acute upper respiratory viral infections,sinusitis, perennial rhinitis, and vasomotor rhinitis. Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.001 mg/kg to about 10 mg/kg of acompound, more preferably from about 0.01 mg/kg to about 5 mg/kg.Peroral administration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily. Such doses and frequenciesare also preferred for treating other respiratory conditions, such asotitis media, cough, chronic obstructive pulmonary disease (COPD) andasthma.

Another aspect of this invention involves methods for preventing ortreating glaucoma by administering a safe and effective amount of asubject compound to a mammal experiencing or at risk of experiencingglaucoma. If administered systemically, each administration of a dose ofthe subject compound preferably administers a dose within the range offrom about 0.001 mg/kg to about 10 mg/kg of a compound, more preferablyfrom about 0.01 mg/kg to about 1 mg/kg, more preferably still from about0.01 mg/kg to about 0.1 mg/kg. If intraocular dosing is used thenpreferably one administers a composition such as an eyedrop, comprisingfrom about 0.0001% to about 5% of a subject compound, more preferablyfrom about 0.01% to about 0.5% of the compound. Determination of theexact dosage and regimen is within the purview of the skilled artisan.Intraocular administration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily.

Another aspect of this invention involves methods for preventing ortreating gastrointestinal disorders, such as diarrhea, irritable bowelsyndrome, and peptic ulcer by administering a safe and effective amountof a subject compound to a mammal experiencing or at risk ofexperiencing gastrointestinal disorders. Each administration of a doseof the subject compound preferably administers a dose within the rangeof from about 0.001 mg/kg to about 10 mg/kg of a compound, morepreferably from about 0.01 mg/kg to about 5 mg/kg. Peroraladministration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily.

Another aspect of this invention involves methods for preventing ortreating migraine, by administering a safe and effective amount of asubject compound to a mammal experiencing or at risk of experiencingmigraine. Each administration of a dose of the subject compoundpreferably administers a dose within the range of from about 0.001 mg/kgto about 10 mg/kg of a compound, more preferably from about 0.01 mg/kgto about 5 mg/kg. Peroral, intranasal, or parenteral administration ofsuch doses is preferred. The frequency of administration of a subjectcompound according to this invention is preferably from about once toabout six times daily, more preferably from about 2 times to about 4times daily. The frequency of parenteral dosing of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about 2 times to about 4 times dailyor by infusion to the desired effect.

Another aspect of this invention involves methods for preventing ortreating disorders related to sympathetic nervous system activity, suchas hypertension, myocardial ischemia, cardiac reperfusion injury,angina, cardiac arrhythmia, and benign prostatic hypertrophy, byadministering a safe and effective amount of a subject compound to amammal experiencing or at risk of experiencing these diseases ordisorders. Each administration of a dose of the subject compoundpreferably administers a dose within the range of from about 0.001 mg/kgto about 10 mg/kg of a compound, more preferably from about 0.01 mg/kgto about 5 mg/kg. Peroral and parenteral administration of such dosesare preferred. The frequency of per oral administration of a subjectcompound according to this invention is preferably from about once toabout six times daily, more preferably from about 2 times to about 4times daily. The frequency of parenteral dosing of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about 2 times to about 4 times dailyor by infusion to the desired effect.

Another aspect of this invention involves methods for preventing ortreating pain, by administering a safe and effective amount of a subjectcompound to a mammal experiencing or at risk of experiencing pain. Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.001 mg/kg to about 10 mg/kg of acompound, more preferably from about 0.01 mg/kg to about 5 mg/kg.Peroral or parenteral administration of such doses is preferred. Thefrequency of administration of a subject compound according to thisinvention is preferably from about once to about six times daily, morepreferably from about 2 times to about 4 times daily. The frequency ofparenteral dosing of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily or by infusion to the desiredeffect.

Another aspect of this invention involves methods for preventing ortreating substance abuse and the abstinence syndrome resulting fromwithdrawal of these substances, such as alcohol and opiates, byadministering a safe and effective amount of a subject compound to amammal experiencing or at risk of experiencing substance abuse orwithdrawal symptoms. Each administration of a dose of the subjectcompound preferably administers a dose within the range of from about0.001 mg/kg to about 10 mg/kg of a compound, more preferably from about0.01 mg/kg to about 5 mg/kg. Peroral administration of such doses ispreferred. The frequency of administration of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about 2 times to about 4 times daily.

COMPOSITIONS AND METHODS EXAMPLES

The following non-limiting examples illustrate the compositions andmethods of use of this invention.

Example A Oral Tablet Composition

    ______________________________________                                                                Amount per                                              Ingredient tablet (mg)                                                      ______________________________________                                        Subject Compound 4        20.0                                                  Microcrystalline cellulose (Avicel PH 102                                                                     ®) 80.0                                   Dicalcium phosphate 96.0                                                      Pyrogenic silica (Cab-O-Sil ®) 1.0                                        Magnesium stearate 3.0                                                        Total = 200.0 mg                                                            ______________________________________                                    

One tablet is swallowed by a patient with nasal congestion. Thecongestion is substantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example B Chewable Tablet Composition

    ______________________________________                                                                Amount per                                              Ingredient tablet (mg)                                                      ______________________________________                                        Subject Compound 1        15.0                                                  Mannitol 255.6                                                                Microcrystalline cellulose (Avicel PH 101                                                                     ®) 100.8                                  Dextrinized sucrose (Di-Pac ®) 199.5                                      Imitation orange flavor 4.2                                                   Sodium saccharin 1.2                                                          Stearic acid 15.0                                                             Magnesium stearate 3.0                                                        FD&C Yellow #6 dye 3.0                                                        Pyrogenic silica (Cab-O-Sil ®) 2.7                                        Total = 600.0 mg                                                            ______________________________________                                    

One tablet is chewed and swallowed by a patient with nasal congestion.The congestion is substantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example C Sublingual Tablet Composition

    ______________________________________                                                                Amount per                                              Ingredient tablet (mg)                                                      ______________________________________                                        Subject Compound 5        2.00                                                  Mannitol 2.00                                                                 Microcrystalline cellulose (Avicel PH 101                                                                     ®) 29.00                                  Mint flavorants 0.25                                                          Sodium saccharin 0.08                                                         Total = 33.33 mg                                                            ______________________________________                                    

One tablet is placed under the tongue of a patient with nasal congestionand allowed to dissolve. The congestion is rapidly and substantiallydiminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example D Intranasal Solution Composition

    ______________________________________                                        Ingredient      Composition (% w/v)                                           ______________________________________                                        Subject Compound 3                                                                             0.20                                                           Benzalkonium chloride  0.02                                                   Thimerosal   0.002                                                            d-Sorbitol  5.00                                                              Glycine  0.35                                                                 Aromatics   0.075                                                             Purified water q.s.                                                           Total = 100.00                                                              ______________________________________                                    

One-tenth of a mL of the composition is sprayed from a pump actuatorinto each nostril of a patient with nasal congestion. The congestion issubstantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example E Intranasal Gel Composition

    ______________________________________                                        Ingredient        Composition (% w/v)                                         ______________________________________                                        Subject Compound 1                                                                               0.10                                                         Benzalkonium chloride  0.02                                                   Thimerosal   0.002                                                            Hydroxypropyl methylcellulose  1.00                                           (Metolose 65SH4000 ®)                                                     Aromatics  0.06                                                               Sodium chloride (0.65%) q.s.                                                  Total = 100.00                                                              ______________________________________                                    

One-fifth of a mL of the composition is applied as drops from a dropperinto each nostril of a patient with nasal congestion. The congestion issubstantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example F Inhalation Aerosol Composition

    ______________________________________                                        Ingredient        Composition (% w/v)                                         ______________________________________                                        Subject Compound 2                                                                               5.0                                                          Alcohol  33.0                                                                 Ascorbic acid  0.1                                                            Menthol  0.1                                                                  Sodium Saccharin  0.2                                                         Propellant (F12, F114) q.s.                                                   Total = 100.0                                                               ______________________________________                                    

Two-puffs of the aerosol composition is inhaled from a metered-doseinhaler by a patient with asthma. The asthmatic condition is effectivelyrelieved.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example G Topical Ophthalmic Composition

    ______________________________________                                        Ingredient           Composition (% w/v)                                      ______________________________________                                        Subject Compound 5     0.10                                                     Benzalkonium chloride   0.01                                                  EDTA   0.05                                                                   Hydroxyethylcellulose (Natrosol M ®)   0.50                               Sodium metabisulfite   0.10                                                   Sodium chloride (0.9%) q.s.                                                   Total = 100.0                                                               ______________________________________                                    

One-tenth of a mL of the composition is administered directly into eacheye of a patient with glaucoma. The intraocular pressure issubstantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example H Oral Liquid Composition

    ______________________________________                                        Ingredient         Amount/15 mL Dose                                          ______________________________________                                        Subject Compound 4      15     mg                                               Chlorpheniramine maleate 4 mg                                                 Propylene glycol 1.8 g                                                        Ethanol (95%) 1.5 mL                                                          Methanol 12.5 mg                                                              Eucalyptus oil 7.55 mg                                                        Flavorants 0.05 mL                                                            Sucrose 7.65 g                                                                Carboxymethylcellulose (CMC) 7.5 mg                                           Microcrystalline cellulose and 187.5 mg                                       Sodium CMC (Avicel RC 591 ®)                                              Polysorbate 80 3.0 mg                                                         Glycerin 300 mg                                                               Sorbitol 300 mg                                                               FD&C Red #40 dye 3 mg                                                         Sodium saccharin 22.5 mg                                                      Sodium phosphate monobasic 44 mg                                              Sodium citrate monohydrate 28 mg                                            Purified Water     q.s.                                                       Total =                 15     mL                                             ______________________________________                                    

One 15 mL dose of the liquid composition is swallowed by a patient withnasal congestion and runny nose due to allergic rhinitis. The congestionand runny nose are effectively reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example J Oral Liquid Composition

    ______________________________________                                                                 Amount/15                                              Ingredient mL Dose                                                          ______________________________________                                        Subject Compound 2         30 mg                                                Sucrose 8.16 g                                                                Glycerin  300 mg                                                              Sorbitol  300 mg                                                              Methylparaben 19.5 mg                                                         Propylparaben  4.5 mg                                                         Menthol 22.5 mg                                                               Eucalyptus oil  7.5 mg                                                        Flavorants 0.07 mL                                                            FD&C Red #40 dye  3.0 mg                                                      Sodium saccharin   30 mg                                                      Purified water q.s.                                                           Total =   15 mL                                                             ______________________________________                                    

One 15 mL dose of the alcohol-free liquid medication is swallowed by apatient with nasal congestion. The congestion is substantiallydiminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example K Oral Tablet Composition

    ______________________________________                                                           Amount per                                                   Ingredient tablet (mg)                                                      ______________________________________                                        Subject Compound 1     4                                                        Microcrystalline cellulose, NF 130                                            Starch 1500, NF 100                                                           Magnesium stearate, USP 2                                                     Total 236 mg                                                                ______________________________________                                    

One tablet is swallowed by a patient with migraine. The pain and aura ofmigraine is substantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example L Oral Tablet Composition

    ______________________________________                                                             Amount per                                                 Ingredient tablet (mg)                                                      ______________________________________                                        Subject Compound 2      12                                                      Hydroxypropyl methylcellulose, USP 12                                         Magnesium stearate, USP 2                                                     Lactose anhydrous, USP 200                                                    Total =  226 mg                                                             ______________________________________                                    

For the relief of pain. Adults 12 and over take one tablet every twelvehours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example M Oral Caplet Composition

    ______________________________________                                                             Amount per                                                 Ingredient tablet (mg)                                                      ______________________________________                                        Naproxen sodium anhydrous, USP                                                                        220                                                     Subject Compound 3 6                                                          Hydroxypropyl methylcellulose, USP 6                                          Magnesium stearate, USP 2                                                     Povidone K-30, USP 10                                                         Talc, USP 12                                                                  Microcrystalline cellulose, NF 44                                             Total =  300 mg                                                             ______________________________________                                    

For relief of symptoms associated with the common cold, sinusitis, orflu including nasal congestion, headache, fever, body aches, and pains.Adults 12 and over take two caplets every twelve hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example N Oral Tablet Composition

    ______________________________________                                                             Amount per                                                 Ingredient tablet (mg)                                                      ______________________________________                                        Subject Compound 4      6                                                       Hydroxypropyl methylcellulose, USP 6                                          Silicon dioxide, colloidal, NF 30                                             Pregelatinized starch, NF 50                                                  Magnesium stearate USP 4                                                      Total =  96 mg                                                              ______________________________________                                    

For reatment of benign prostatic hypertrophy. Take one tablet per day.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example O Oral Tablet Composition

    ______________________________________                                                             Amount per                                                 Ingredient caplet (mg)                                                      ______________________________________                                        Subject Compound 5      6                                                       Hydroxypropyl methylcellulose, USP 6                                          Magnesium stearate, USP 2                                                     Povidone K-30, USP 10                                                         Talc, USP 12                                                                  Microcrystalline cellulose, NF 44                                             Total =  80 mg                                                              ______________________________________                                    

For use in the treatment of alcoholism or opiate addiction. Adults 12and over take two caplets every twelve hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example P Oral Tablet Composition

    ______________________________________                                        Ingredient           Amount per tablet (mg)                                   ______________________________________                                        Subject Compound 1   6                                                          Hydroxypropyl methylcellulose, USP 12                                         Magnesium stearate, USP 2                                                     Povidone K-30, USP 10                                                         TaIc, USP 12                                                                  Microcrystalline cellulose, NF 44                                             Total =  86 mg                                                              ______________________________________                                    

For the treatment of ulcer and hyperacidity. Take two tablets asappropriate.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example Q Oral Tablet Composition

    ______________________________________                                                           Amount per tablet (mg)                                       Ingredient Amount                                                           ______________________________________                                        Component                                                                       Subject Compound 5 10 mg/ml carrier                                           Carrier:                                                                      Sodium citrate buffer with (percent                                           by weight of carrier):                                                        Lecithin 0.48%                                                                Carboxymethylcellulose 0.53                                                   Povidone 0.50                                                                 Methyl paraben 0.11                                                           Propyl paraben 0.011                                                        ______________________________________                                    

For the reduction of cardiac reperfusion injury.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example R Oral Liquid Composition

    ______________________________________                                        Ingredient           Amount/fl oz Dose (mg)                                   ______________________________________                                        Acetaminophen, USP   1000                                                       Doxylamine succinate, USP 12.5                                                Dextromethorphan hydrobromide, USP 30                                         Subject Compound 2 6                                                          Dow XYS-40010.00 resin 3                                                      High fructose corn syrup 16000                                                Polyethylene glycol, NF 3000                                                  Propylene glycol, USP 3000                                                    Alcohol, USP 2500                                                             Sodium citrate dihydrate, USP 150                                             Citric acid, anhydrous, USP 50                                                Saccharin sodium, USP 20                                                      Flavor 3.5                                                                    Purified water, USP 3500                                                      Total =  29275 mg/fl oz                                                     ______________________________________                                    

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example S Oral Liquid Composition

    ______________________________________                                        Ingredient           Amount/fl oz Dose (mg)                                   ______________________________________                                        Naproxen sodium anhydrous, USP                                                                     220                                                        Doxylamine succinate, USP 12.5                                                Dextromethorphan hydrobromide, USP 30                                         Subject Compound 1 6                                                          Dow XYS-40010.00 resin 3                                                      High fructose corn syrup 16000                                                Polyethylene glycol, NF 3000                                                  Propylene glycol, USP 3000                                                    Alcohol, USP 2500                                                             Sodium citrate dihydrate, USP 150                                             Citric acid, anhydrous, USP 50                                                Saccharin sodium, USP 20                                                      Flavor 3.5                                                                    Purified water, USP 3800                                                      Total =  28795 mg/fl oz                                                     ______________________________________                                    

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Composition Example T

A composition for parenteral administration, according to thisinvention, is made comprising:

    ______________________________________                                        Component           Amount                                                    ______________________________________                                        Subject Compound I  10 mg/ml carrier                                            Carrier:                                                                      Sodium citrate bufter with (percent                                           by weight of carrier):                                                        Lecithin 0.48%                                                                Carboxymethylcellulose 0.53                                                   Povidone 0.50                                                                 Methyl paraben 0.11                                                           Propyl paraben 0.011                                                        ______________________________________                                    

The above ingredients are mixed, forming a solution. Approximately 2.0ml of the solution is administered, intravenously, to a human subjectsuffering from septic or cardiogenic shock. The symptoms subside.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example U Oral Tablet Composition

    ______________________________________                                        Ingredient           Amount per tablet (mg)                                   ______________________________________                                        Subject Compound 5   10                                                         Hydroxypropyl methylcellulose, USP 12                                         Magnesium stearate, USP 2                                                     Povidone K30 USP 10                                                           Talc, USP 12                                                                  Microcrystalline cellulose, NF 44                                             Total =  90 mg                                                              ______________________________________                                    

For the treatment of cardiac arrhythmia. Take as prescribed.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example V Oral Tablet Composition

    ______________________________________                                        Ingredient          Amount per tablet (mg)                                    ______________________________________                                        Subject Compound 1  4                                                           Microcrystalline cellulose, NF 130                                            Starch 1500, NF 100                                                           Magnesium stearate, USP 2                                                     Total 236 mg                                                                ______________________________________                                    

For the treatment of congestive heart failure. Take as prescribed.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Modification of the preceding embodiments is within the scope of theskilled artisan in formulation, given the guidance of the specificationin light of the state of the art.

Other examples of combination actives are contemplated. Examples ofmedicaments which can be combined with the primary active are includedin U.S. Pat. No. 4,552,899 to Sunshine, et al., hereby incorporated byreference. All other references referred to throughout thisspecification are hereby incorporated by reference.

While particular embodiments of this invention have been described, itwill be obvious to those skilled in the art that various changes andmodifications of this invention can be made without departing from thespirit and scope of the invention. It is intended to cover, in theappended claims, all such modifications that are within the scope ofthis invention.

What is claimed is:
 1. A method for preventing or treating a disordermodulated by alpha-2 adrenoceptors, wherein the disorder is selectedfrom the group consisting of nasal congestion, otitis media, sinusitis,asthma, pain, migraine, benign prostatic hypertrophy and elevatedintracranial pressure, by administering to a mammal in need of suchtreatment, a safe and effective amount of an alpha-2 adrenoreceptoragonist compound of formula: ##STR8## wherein: (a) R is unsubstitutedalkanyl or alkenyl having from 1 to about 3 carbon atoms; and(b) R' isselected from the group consisting of hydrogen; unsubstituted alkanyl oralkenyl having from 1 to about 3 carbon atoms; unsubstituted alkythio oralkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; and halo.2. A pharmaceutical composition comprising:(a) the compound of formula;##STR9## wherein: (1) R is unsubstituted alkanyl or alkenyl having from1 to about 3 carbon atoms; and(2) R' is selected from the groupconsisting of hydrogen; unsubstituted alkanyl or alkenyl having from 1to about 3 carbon atoms; unsubstituted alkythio or alkoxy having from 1to about 3 carbon atoms; hydroxy; thiol; and halo; (b) apharmaceutically acceptable carrier; and (c) further comprising one ormore actives chosen from the group consisting of an antitussive, mastcell stabilizer, LT antagonist, expectorant/muycolytic, antioxidant orradical inhibitor, steroid, bronchodilator, antiviral, analgesic,antiinflammatory, gastrointestinal active and ocular active.
 3. Thepharmaceutical composition according to claim 2 wherein said one or moreactive is an antihistamine.
 4. The pharmaceutical composition accordingto claim 2 wherein said one or more active is an antuinflamatory.
 5. Thepharmaceutical composition according to claim 2 wherein said one or moreactive is an antitussive.
 6. The pharmaceutical composition according toclaim 2 wherein said one or more active is a mast cell stabilizer. 7.The pharmaceutical composition according to claim 2 wherein said one ormore active is an LT antagonist.
 8. The pharmaceutical compositionaccording to claim 2 wherein said one or more active is anexpectorant/mucolytic.
 9. The pharmaceutical composition according toclaim 2 wherein said one or more active is an antioxidant or radicalinhibitor.
 10. The pharmaceutical composition according to claim 2wherein said one or more active is a steroid.
 11. The pharmaceuticalcomposition according to claim 2 wherein said one or more active is abronchodilator.
 12. The pharmaceutical composition according to claim 2wherein said one or more active is an antiviral.
 13. The pharmaceuticalcomposition according to claim 2 wherein said one or more active is ananalgesic.
 14. The pharmaceutical composition according to claim 2wherein said one or more active is a gastrointestinal active.
 15. Thepharmaceutical composition according to claim 2 wherein said one or moreactive is an ocular active.
 16. The pharmaceutical composition accordingto claim 2 wherein R' is selected from the group consisting of:hydrogen, methyl, ethyl, methoxy, chloro, and bromo.
 17. Thepharmaceutical composition according to claim 16 wherein R is alkanyl.18. The pharmaceutical composition according to claim 16 wherein R ismethyl.